Antimicrobial resistance (AMR) is a major, growing health and economic problem worldwide due to the appearance of newer, pathogenic bacterial strains. As the worldwide population began overusing antibiotics in the clinic, for livestock, and in everyday life (e.g. food and hand soap), bacteria began evolving defense mechanisms. As a result, it is estimated that more than 2 million people in the United States are sickened every year with AMR infections with at least 23,000 resulting deaths.
The bacterial enzyme, N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a protein involved in the lysine and diaminopimelic acid (DAP) biosynthetic pathway, and is critical for the synthesis of the bacterial cell wall. See Gillner, et al. Bioorg. Med. Chem. Lett., 2009, 19, 6350-635; Scapin, et al. Adv. Enzymol. Relat. Areas Mol. Biol., 1998, 72, 279-32; Gilvarg, et al. J. Biol. Chem., 1959, 234, 2955-2959. Small molecules that are able to block DapE activity are toxic to bacteria, allowing them to function effectively as antibiotics. Traditional DapE inhibitors, however, are suboptimal because they contain thiol moieties. The thiol moieties are prone to oxidation and also exhibit promiscuous selectivity because they often bind tightly to any zinc-containing enzyme. Also, at least one thiol-containing antimicrobial, captopril, was found to be independent of DapE inhibition. See Creus et al., Bioinorg. Chem. Appl., 2011, 306465.
Metallo-β-lactamases (MBLs) are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs conferring resistance to the bacteria. New Delhi metallo-β-lactamase 1 (NDM-1) is a zinc-dependent metallohydrolase found in bacteria that confers resistance to commonly-administered antibiotics, including penicillins, cephalosporins, and carbapenems. See Rolain, J. M.; Parola, P.; Cornaglia, G. Clinical Microbiology and Infection 2010, 16, 1699-1701. Horizontal gene transfer has enabled the blaNDM-1 gene to spread between species, facilitating the development of multi-drug resistant bacterial strains. Id. Bacteria carrying the blaNDM-1 gene have been found on all continents, and consequently, NDM-1 has gained international attention as a clinically relevant pharmaceutical target. Id. Known inhibitors of MBLs, such as thiol-containing inhibitors, are prone to oxidation and challenges with selectivity due to the thiol moiety. See Li et al., Bioorganic & Medicinal Chemistry 24:386-389 (2014).
Therefore, new compounds capable of inhibiting DapE and MBLs (e.g., NDM-1) are greatly needed.